Phenthiazine derivatives in pharmaceutical compositions

ABSTRACT

Phenthiazine derivatives of the formula: WHEREIN R represents an alkyl, alkenyl or alkynyl group containing 7-17 carbon atoms, are very active as long acting neuroleptics, anti-emetics and tranquilisers.

1111. 3,879,55 1451 Apr.` 22,1197

1075.976 111965,11101`n11. .;1.v 26o/:13

PHENTHiA'zlNgRI'vAT/ES 'Pl'j'ihzp derivatiyes of theformula:

Int. CI.....

U.s.`fc1;...;...;....1.....;; A24/247;'26o/247141" Mosher 3.1941733 7/1965 Yale 26o/2` '3,350,268 l0/I967 Yale ..260/2` Primary Emminr-Stanlejy J. Friedman An'omey. Agent, or F ifm-Stevens. Davis, Miller &

ABSTRACT 1 y y k','11 I1`11 1 111611127/00` --whe'em R represents a" al l l en) o' d Vmld Search ..1 26o/243A; 4241247 liscrs. y

3 Claims. No Drawings This applicationfisa continuatoniapplication of our copendng application Ser. No; 49,192 now abandoned which itself is a continuation-in-partof ourcopendin g application Ser, No. 7 l7 ,0l2 ledfMaL 28. .1968.

This invention-relates'to newfther'apeutically useful 1 t `ihcfcordingtda furtherlfeatureof the invention. thi -Yl0V phenthiazne derivatives of formula larejprepared bj phenthiazine derivatives;toprocesses for'their preparation and pharr'nceutical'compositions containing According-ftp ythe:l prcsent'iinven'tion. there are'provided the new p formula:

wherein' R.representsastiaighrr.baneheajiiikymke- 25 phonylox'yfor toluene-pfsulphonyloxy residue)A with a defined.

When the symbol Xiepresentsa halogen atom."in

purticularchlorine. or an'. imidazolyl` alkanoyloxy, alkenoyloxy or alkynoyloxyI group,A it is advantageous to carry out the process in an inertorganicsolvent (for ex# t ample benzene, toluene,` or chloroform and y'preferably at thevb'oiling point ofthsolvent employed inlthelabsence or presence of an inorganicl 'or :organic acidbinding agent.

enthi'au'zine..o'fzthef'4 ,Y 'aceordmggto theforegoing processesmaygbepurie `by,physical methods such'as'distillation.-fcrystallisatic presnis'neaad@indium formula Ref-,CO-'O Ofi-l- Rbeinglas hereinbefo re V y andjranquillsershey have given good results as sul 1 if "T theproces's henthiazinederivatives A of the 'general n 2 t When the symbol X represents the hydroxy group the process is generally carried out in an inert organii solvent in thepresence of either a strong acid or a Lewis acid or of dieyclohexylcarbodiimide. V

I Whenjthe symbol Xrepresents anfalkox'y group. thi processis generallycar'ried outin an'inert organic sol ventsuch` as toluene'and the alcohol formed is remove( byaicotropiedistillation. l.

which comprises rcacting aphenthiazine o l yla'lkalijinetai sul; or in acia'nf the formula R-Cof-oi ablyfat'th-elbilingpointofthe solventiemployed. j

orchrornatogr`aphy.`f or b'yfchemical methods. such z the formationofsalts.: crystallisationfof the 4salts'and di f'o'rnposition of them in anallaIinemedium; ln the sa I hemi4a11mfhlomthejnaiq-leofihe 'nippf the sali -fii'nmaterial.'the only'f'requirement being that the sa V.must.be'jwellfdefined'and readily crystallisable..

5o f acids l'onthe new Y'plien'tltiziiief dertvativesin appr which may-.have a straightor `branched hydroeariponi;55`

k p rtat v entsifAs organic solvents theremay be use forfe VrnpleQalcoholsQethersl'keitones or chlornat| liydi" A arbons; 1 "l`he'salt which `ist'ornied `is precipitate 'if ncessaryiaiter'eoneentratin'lotf'its solution( and parated byltration ofdecantation.

The phe'nthiazine derivatiifes of the present inventi interesting pharmacodyn'aineproperties; they a 'veiy*'acti'vel as long-aeting 'rieuiio'lepticsg antiemeti -in physiological experiments withanimals at doses 0.005 to 1.0 mgl/kg. of animal weight by subcutaneo olf-intramuscular administration. For example. t compounds of formula l have been found to have a pi 5 longed antagonistic; effect against ernesis caused apornbrphine in the'dog. A subcutaneous dosage of o of thenewgcornpounds (as the free base) of 0.05 to rng.lkg`.reduces the number of vom its caused by subc 3,879,551 3 4 tuneous administration of 0.1 mg./kg. of apomorphine dimethylsulphamoyl-l0-{3-[4(2 r t l by 50 percent for from 10 to 50 days. The compounds lauroyloxyethyl)piperidinolpropyl} phenthiazineoxaof formulal have shown no toxic effects ut dosages at lute (13.1 gil.' melting at about 130C. is obtained. t

least ushigh us 0.8 mgJkg. Preferred compounds ure Luuroyl chloride employed as starting material (b.p. 3-dmethylsulphumoyl-l0-{3-[4-(2- 5 l l0Cl2mm.l 'lg) is prepared according to H. Richet. pulmtoyloxyethyl)ppcrdinolpropy-phenthinzine. BulLSoc. ChimpFr.. (19461` 52. 3-dimethylsulphamoyl.10-{3[.4f(2undecl0' I f l enoyloxycthyl)pperdino]propyl} phenthiuzine` 3- .gggmrevf phent'hiaiine'MJS hydroxyethyl)piperidinolpropy phenthiazine (3.3 g) t a concentration of 0.25 to l percent by weight.- and.

` if necessary. subsequently sterilizing the solution obtained by filtration through a bacteriological filter.

The following Examples illustrate the preparation of pharmaceutical compositions according to the invention.

` EXAMPLE xvm lauroylox'yethyl)piperidino]propyl} phenthiazine oxalate (|70 mg.) is treated at ambient temperature with a mixture of a l'percent aqueous solution of sodium bicarbonate'( 'l lOcc.) and diethyl ether (50 cc.). After dissolution` the ethereal phase is decanted, washed with distilled water (2 X 50 cc.) until neutral. and then is reacted withjfl 2.2idimethylhexadecanoyl chloride44 (2.l3g`.)` in toluene ('30 cc':.)`.1l 'The-:crude.'productfis chromatographed through a column (115cm. in diarrie-V ter) of neutral alumina (40-g.)tan`d elut` ed with a mix-r f ture oflcyelohe'xane and-ethyl ace't ate 8-2 by volume) The base"`obtained afterchromatographyf(4.70 g..)'lis dissolvedin refluxing ethyl)acetate-(125cc.) .and .then

2,Z-Dimethylhexadecanoyl *chloride ispreparedgby the dimethylhexadecanoie acid:

2.2Dimethylhe'xadecanoic acid l' isi-prepared Iaccording to Buu-Hoi et col|., Z-`Physiol.. Chem. 279` A84 Thefpresent inventionV includes within itsscope phari' tained.

dried over anhydrous magnesium sulphate. After concentration'undergreduced pre ssure"(20'mm. Hg.)` the residue |50 nig.) isdisslved in ses'ame oil( l5 cc.) at 40C.`Aft er 'cooling to ambient temperaturelfa clear yellow'v solution` containing l percent of 3- dimethylsulphanioyl-l0-{3[ 4-( 2 lauroyloxyfethyl)piperidinolpropyll phenthiazine is obenoyloxyethyl)pipcridino]propyl}phenthia2ine (2.5 g.)

is'dis'sfolved at 40C 'in neutraliser! sesame oil (|00 cc.) with'jagitati'on.;'After'cooling, the yellow solution ob- ,.tainedjisfilteredthrough a bacteriological filter under afnitrogen`pressureeof2-kgJcm The filtered solution c. ofsolution per ampoule. The filled ampoules are sealed undernitrogen.

.v ,."Theresultingampoules each contain |00 mg. of acmaceutical compositionscontaining. as active ingredi-V ent. atleast one of thephenthiazinederivatives of formula `l in association withajpharmaceutical carrier, or coating. The invention includes'espccially such preparations made up for parenteral` inparticular intramus- Y as acttveingredient,a therapeutically acttve'amount of a phenthiazine derivative of the formula:

cular or subcutaneous;administration(4 Y Preparations for parenteral administration `include sterile non-aqueous'solutions'.Examples 4of suitable non-aqueoussolvents are injectable vegetable oils, suchlas sesame oil or" olive oil.` and injectablev organic esters such as ethyl oleate'.;.|`he preparations maybe stcrilised by.for,example, filtration through abacteria` retaining filter, by incorporation inthe compositions of stc'rilisingagcnts. by irradiatiomor by heating.) The percentage of active ingredient in the compositions of the inventlon may bc `vut-led. it'belng necessary that |t should constitute u proportion auch vtltata sultable dosage shall be-obtained. The dosage depends `on the desired therapeutic'effectand on the durationof the treatment. ln humanftherapy the composition should generally be administered so as to give an adult between 5 and |00 mg. ofactive substance at the rate of one intramuscular injection every-2 to'4 weeks.;

Because of the prolonged anti-emetic effectl of the new phenthiazine derivatives mentioned above. it is often desirable to administer the compounds by intra- Y muscular or subcutaneous injection as depot preparations. Such preparations may be made by conventional methods, e.g., by dissolving the new bases vof formula l in an injectable water-insoluble vegetable oil,` e.g.` in

fusing pa|mito loxyethyl)piperidinolpropyphenthiazine. E mp. 6| -62C., ampoules are obtained each containing tiveprfoduct readyfor intramuscular administration.

' ExAMPLE'xx' fproceefdingas described( in Example XIX but |00 mg. of active product.

We claim:' L Apharmaceutical composition which comprises` sozidca) 2 Lgs-Oe' (cszi-o-coat maceutical carrier.

2. composition according to claim l in the form o1 a solutionofthe phenthiazine derivative in an injecta- :ble wateiffinsoluble vegetable oil.

3; l'l`he""cor npositionlaccording to claim 1 comprising at least one phenthiazine' selected from the group con `sistin'g ofzv t Ill-dimethylsulphamo l-lO- {3-[4(2-lauroyloxyethyl) piperidinolpropyl phenthiazine` 3dimethylsulphamoyl-l0-{3f[4(2-undec-l0'enoyloityethyl)Lpiperidino]propyl}phenthiazine` and, 3-dimethylsulphamoyll 0- {3-l 4( 2palmitoyloxye thyl)piperidino]propyl} phenthiazine.

Umm@ STATES MTENT om@ @ERTHCATE QBRECTUN Patent No, 3,879,551 Dated April 22, 1975 Inventor(s) Jean-Claude Ren Georges BLONDEL et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the heading, for vthe residence of che second inventor (Fouch) read -Bourg1aReine-.

In the Foreign Application Priority Data, for the second item read --April 6, 19'70 Sweden 4156/68 (filed March 28, 1968, as amended April 6, 1970) gned and @als time A ttes t.'

RUTH C. MASON C. MARSHALL DANN .'1Itest1`ng Officer ('mnmissnmr u l'lalents und Trademarks 

1. A PHARMACEUTICAL COMPOSITION WHICH COMPRISES, AS ACTIVE INGREDIENT A THERAPEUTICALLY ACTIVE AMOUNT OF A PHENTHIAZINE DERIVATIVE OF THE FORMULA
 1. A pharmaceutical composition which comprises, as active ingredient, a therapeutically active amount of a phenthiazine derivative of the formula:
 2. A composition according to claim 1 in the form of a solution of the phenthiazine derivative in an injectable water-insoluble vegetable oil. 